JP2004507528A - Methods and intermediates for preparing retroviral protease inhibitors - Google Patents
Methods and intermediates for preparing retroviral protease inhibitors Download PDFInfo
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- JP2004507528A JP2004507528A JP2002523467A JP2002523467A JP2004507528A JP 2004507528 A JP2004507528 A JP 2004507528A JP 2002523467 A JP2002523467 A JP 2002523467A JP 2002523467 A JP2002523467 A JP 2002523467A JP 2004507528 A JP2004507528 A JP 2004507528A
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 239000000543 intermediate Substances 0.000 title abstract description 6
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 2
- 230000001177 retroviral effect Effects 0.000 title 1
- AMPWQTJNJASABL-UHFFFAOYSA-N 1,6-diphenylhexan-1-amine Chemical compound C=1C=CC=CC=1C(N)CCCCCC1=CC=CC=C1 AMPWQTJNJASABL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- -1 2,6-dimethylphenoxyacetyl Chemical group 0.000 abstract description 42
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- 239000012279 sodium borohydride Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- FOJWLLXWJOVURY-UHFFFAOYSA-N 5-(2,2-dibenzylhydrazinyl)-1,6-diphenylhexan-3-ol Chemical compound OC(CCc1ccccc1)CC(Cc1ccccc1)NN(Cc1ccccc1)Cc1ccccc1 FOJWLLXWJOVURY-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000004030 hiv protease inhibitor Substances 0.000 description 3
- 229940043131 pyroglutamate Drugs 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- MTOBBJCWGZMHGE-UHFFFAOYSA-N 2-(2,6-dimethylphenoxy)acetyl chloride Chemical compound CC1=CC=CC(C)=C1OCC(Cl)=O MTOBBJCWGZMHGE-UHFFFAOYSA-N 0.000 description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 229960004525 lopinavir Drugs 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- CVUOJBKULXTCRU-ZETCQYMHSA-N (2s)-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanoyl chloride Chemical compound CC(C)[C@@H](C(Cl)=O)N1CCCNC1=O CVUOJBKULXTCRU-ZETCQYMHSA-N 0.000 description 1
- IVYLNCUETJNNJU-AYRMWSDDSA-N (z,2s)-5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one Chemical compound O=C([C@H](CC=1C=CC=CC=1)N(CC=1C=CC=CC=1)CC=1C=CC=CC=1)\C=C(/N)CC1=CC=CC=C1 IVYLNCUETJNNJU-AYRMWSDDSA-N 0.000 description 1
- PCNUMNNUBZHHKG-UHFFFAOYSA-N 1,6-diphenylhexan-2-amine Chemical compound NC(CCCCC1=CC=CC=C1)CC1=CC=CC=C1 PCNUMNNUBZHHKG-UHFFFAOYSA-N 0.000 description 1
- BXINIXQKBCSKKR-UHFFFAOYSA-N 1-phenylhexylbenzene Chemical compound C=1C=CC=CC=1C(CCCCC)C1=CC=CC=C1 BXINIXQKBCSKKR-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 108010010369 HIV Protease Proteins 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- AIDS & HIV (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
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Abstract
本発明は（（２Ｓ，３Ｓ，５Ｓ）−２−（２，６−ジメチルフェノキシアセチル）−アミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロピリミド−２−オニル）−３−メチル−ブタノイル）アミノ−１，６−ジフェニルヘキサンおよびその類似体の合成に使用する方法および中間体を提供する。The present invention relates to ((2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) -amino-3-hydroxy-5- (2S- (1-tetrahydropyrimid-2-onyl) -3-methyl Provided are methods and intermediates used in the synthesis of -butanoyl) amino-1,6-diphenylhexane and analogs thereof.
Description
【０００１】
技術分野
本発明は、ＨＩＶプロテアーゼ阻害薬の合成に使用する方法および中間体に関する。
【０００２】
発明の背景
ヒト免疫不全ウイルス（ＨＩＶ）のプロテアーゼ阻害薬である化合物は、ｉｎ ｖｉｔｒｏおよびｉｎ ｖｉｖｏでのＨＩＶプロテアーゼの阻害に有用であり、さらにＨＩＶ感染の抑制に有用である。ＨＩＶプロテアーゼ阻害薬の例には、次式Ｉの化合物が含まれ、
【０００３】
【化５】
【０００４】
式Ｉの化合物およびその類似体の調製に有用な中間体は、次式ＩＩの化合物である。
【０００５】
【化６】
【０００６】
式ＩＩの化合物の調製方法は、米国特許第５，９１４，３３２号で開示されている。その方法は、次式ＩＩＩの化合物
【０００７】
【化７】
【０００８】
【化８】
【０００９】
好ましい式ＩＩＩの化合物は、Ｐ１およびＰ２がＮ保護基である。最も好ましい式ＩＩＩの化合物は、Ｐ１およびＰ２がどちらもベンジルである。最高に好ましいものは、（２Ｓ，３Ｓ，５Ｓ）−２−Ｎ，Ｎ−ジベンジルアミノ−３−ヒドロキシ−５−アミノ−１，６−ジフェニルヘキサンである式ＩＩＩの化合物である。
【００１０】
好ましい式ＩＶの化合物は、Ｒ３が低級アルキルである。最も好ましい式ＩＶの化合物は、Ｒ３がイソプロピルである。同様に好ましいものは、式ＩＶの化合物の酸塩化物誘導体である。最高に好ましいものは、２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチル酪酸である式ＩＶの化合物および２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイルクロリドである式ＩＶの化合物である。
【００１１】
開示されている方法では、適切な溶媒（酢酸エチルまたは酢酸エチル／ＤＭＦ）中で、塩基としてイミダゾールを用い、（２Ｓ，３Ｓ，５Ｓ）−２−Ｎ，Ｎ−ジベンジルアミノ−３−ヒドロキシ−５−アミノ−１，６−ジフェニルヘキサンを２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイルクロリドと反応させる。しかし、この方法は、中間体の不安定さ、収率の低さ、および触媒被毒を含む数多くの理由のために大規模生産に適さない。特に、この酸塩化物が比較的不安定であり、酸塩化物の調製に塩化チオニルを使用すると、後の反応で使用する触媒を被毒させる不純物がもたらされる。さらに、利用された反応条件下では、アミノ酸側鎖のある程度のラセミ化が起こる。
【００１２】
したがって、上文で定義した式Ｉの化合物を含むＨＩＶプロテアーゼ阻害薬の合成に使用する中間体を調製するための改良された方法が今なお求められている。
【００１３】
発明の開示
本発明は、次式ＩＩの化合物
【００１４】
【化９】
【００１５】
【化１０】
次式Ｖの化合物
【００１６】
【化１１】
【００１７】
本発明の好ましい方法では、Ｐ１およびＰ２はＮ保護基であり、Ｒ３は低級アルキルであり、Ｒ４はイミダゾリルである。本発明の最も好ましい方法では、Ｐ１およびＰ２はどちらもベンジルであり、Ｒ３はイソプロピルであり、Ｒ４はイミダゾリルである。
【００１８】
本発明の方法では、式ＩＩＩの化合物約１．０モルから式Ｖの化合物約１．３モルのモル比で、式ＩＩＩの化合物と式Ｖの化合物を反応させる。好ましい比は、約１．０〜約１．２である。最も好ましい比は、約１．０から約１．１５である。
【００１９】
本発明の方法に適する溶媒は、酢酸イソプロピル、酢酸エチル、テトラヒドロフラン（ＴＨＦ）、メチルｔ−ブチルエーテルなど、不活性溶媒である。本発明の方法に好ましい溶媒は、酢酸エチルである。
【００２０】
本発明の方法は、約１５℃〜約１００℃の温度で実施できる。本発明の方法に好ましい温度は、溶媒の還流温度付近である。本発明の方法に最も好ましい温度は、約７５℃から約８０℃である。
【００２１】
本発明の方法は、水が存在すると加速される。反応混合物中に存在する水の好ましい量は、反応混合物の総体積（ｍＬ）に対する水の量（グラム）の割合で約１％〜約３％（重量／体積）である。
【００２２】
式Ｖの化合物は、酢酸イソプロピル、酢酸エチル、テトラヒドロフラン（ＴＨＦ）、メチルｔ−ブチルエーテルなど、不活性な非プロトン性溶媒中、約１５℃〜約５０℃の温度で、カルボン酸ＩＶ（約１．００モル）とカルボニルジイミダゾール（約１．０５モル）を反応させることによって調製する。酢酸エチル中約１５℃で、カルボン酸ＩＶと、Ｒ４−Ｃ（Ｏ）−Ｒ４、Ｒ４−Ｃ（Ｓ）−Ｒ４、またはＲ４−Ｓ（Ｏ）−Ｒ４［式中、Ｒ４は上記で定義したとおりである］（好ましくはカルボニルジイミダゾール）を反応させることが好ましい。
【００２３】
式Ｖの化合物は単離することもできるが、これを調製し、次いでワンポットプロセスで、式ＩＩＩの化合物と（単離および精製をせずに）反応させることが好ましい。
【００２４】
次いで、Ｐ１およびＰ２がそれぞれベンジルである式ＩＩの化合物を脱ベンジル化することができ、さらに、得られた、Ｐ１およびＰ２がそれぞれ水素である（（Ｓ）−ピログルタミン酸塩としての）式ＩＩの化合物を、（米国特許第５，９１４，３３２号で開示されているような）２，６−ジメチルフェノキシアセチルクロリドと反応させて、ロピナビルを得ることができる。
【００２５】
本明細書では、用語「低級アルキル」は、１〜６個の炭素原子を含む直鎖または分枝鎖の炭化水素基を指す。低級アルキル基の代表例には、たとえば、メチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル、ｓ−ブチル、ｔ−ブチルｎ−ペンチル、１−メチル−ブチル、２，２−ジメチルブチル、２−メチルペンチル、２，２−ジメチルプロピル、ｎ−ヘキシルなどの基が含まれる。
【００２６】
本明細書では、用語「シクロアルキル」は、３〜１０個の炭素原子および１または２個の環を有する脂肪族環系を指す。代表的なシクロアルキル基には、たとえば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、ノルボルナン、ビシクロ［２．２．２］オクタンなどが含まれる。
【００２７】
本明細書では、用語「（シクロアルキル）アルキル」は、低級アルキル基に結合したシクロアルキル基を指す。（シクロアルキル）アルキル基の代表例には、たとえば、シクロヘキシルメチル、シクロペンチルメチル、シクロヘキシルエチル、シクロペンチルエチルなどの基が含まれる。
【００２８】
本明細書では、用語「Ｎ保護基」または「Ｎ保護した」は、アミノ酸またはペプチドのＮ末端を保護する、あるいは合成手順中の望ましくない反応からアミノ基を保護することを意図した基を指す。一般に使用されているＮ保護基は、Ｔ．Ｈ．ＧｒｅｅｎｅおよびＰ．Ｇ．Ｍ．Ｗｕｔｓの「Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ」、第２版、ニューヨーク、Ｊｏｈｎ Ｗｉｌｅｙ＆Ｓｏｎｓ社刊、（１９９１年）で開示されている。Ｎ保護基は、ホルミル、アセチル、プロピオニル、ピバロイル、ｔ−ブチルアセチル、２−クロロアセチル、２−ブロモアセチル、トリフルオロアセチル、トリクロロアセチル、フタリル、ｏ−ニトロフェノキシアセチル、α−クロロブチリル、ベンゾイル、４−クロロベンゾイル、４−ブロモベンゾイル、４−ニトロベンゾイルなど、アシル基；ベンゼンスルホニル、ｐ−トルエンスルホニルなど、スルホニル基；フェニルスルフェニル（フェニル−Ｓ−）、トリフェニルメチルスルフェニル（トリチル−Ｓ−）など、スルフェニル基；ｐ−メチルフェニルスルフィニル（ｐ−メチルフェニル−Ｓ（Ｏ）−）、ｔ−ブチルスルフィニル（ｔ−Ｂｕ−Ｓ（Ｏ）−）など、スルフィニル基；ベンジルオキシカルボニル、ｐ−クロロベンジルオキシカルボニル、ｐ−メトキシベンジルオキシカルボニル、ｐ−ニトロベンジルオキシカルボニル、２−ニトロベンジルオキシカルボニル、ｐ−ブロモベンジルオキシカルボニル、３，４−ジメトキシベンジルオキシカルボニル、３，５−ジメトキシベンジルオキシカルボニル、２，４−ジメトキシベンジルオキシカルボニル、４−メトキシベンジルオキシカルボニル、２−ニトロ−４，５−ジメトキシベンジルオキシカルボニル、３，４，５−トリメトキシベンジルオキシカルボニル、１−（ｐ−ビフェニルイル）−１−メチルエトキシカルボニル、α，α−ジメチル−３，５−ジメトキシベンジルオキシ−カルボニル、ベンズヒドリルオキシカルボニル、ｔ−ブチルオキシカルボニル、ジイソプロピルメトキシ−カルボニル、イソプロピルオキシカルボニル、エトキシカルボニル、メトキシカルボニル、アリルオキシカルボニル、２，２，２−トリクロロエトキシカルボニル、フェノキシカルボニル、４−ニトロ−フェノキシカルボニル、フルオレニル−９−メトキシカルボニル、シクロペンチルオキシカルボニル、アダマンチルオキシカルボニル、シクロヘキシルオキシカルボニル、フェニルチオカルボニルなど、カルバメート形成基；ベンジル、ｐ−メトキシベンジル、トリフェニルメチル、ベンジルオキシメチルなど、アルキル基；ｐ−メトキシフェニルなど；およびトリメチルシリルなど、シリル基を含む。好ましいＮ保護基には、ベンジルなどがある。
【００２９】
以下に実施例を示して本発明をさらに説明する。
【００３０】
実施例１
（２Ｓ，３Ｓ，５Ｓ）−２−Ｎ，Ｎ−ジベンジルアミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロピリミド−２−オニル）−３−メチルブタノイル）アミノ−１，６−ジフェニルヘキサン
Ａ．（２Ｓ，３Ｓ，５Ｓ）−２−Ｎ，Ｎ−ジベンジルアミノ−３−ヒドロキシ−５−アミノ−１，６−ジフェニルヘキサン
水素化ホウ素ナトリウム１１．５グラムをエチレングリコールジメチルエーテル（ＤＭＥ）２９２グラム中に懸濁させ、−５℃以上に冷却した。別のフラスコで、温度を３５℃以下に保ったエチレングリコールジメチルエーテル２８．０グラムにメタンスルホン酸（ＭＳＡ）７０．４グラムをゆっくりと加えた。このＭＳＡ溶液を２５℃以下に冷却し、温度を５℃以下に保った水素化ホウ素ナトリウム懸濁液に移した。別のフラスコで、エチレングリコールジメチルエーテル９１．７グラムとイソプロピルアルコール５０．０グラムの混合物中に２−アミノ−５Ｓ−ジベンジルアミノ−４−オキソ−１，６−ジフェニルヘキサン（米国特許第５，４９１，２５３号）５０ｇｍを溶解させた。この溶液を、温度を２５℃以下に保った水素化ホウ素ナトリウム／ＭＳＡ溶液に移した。フラスコの内容物を１５〜２５℃で１時間以上攪拌した。次いで、内容物を−３℃以下に冷却し、温度を５℃以下に保ちながらトリエタノールアミン５３．０グラムを加えた。この混合物を１５分以上攪拌し、温度を１０℃以下に保ちながら、水素化ホウ素ナトリウム７．１グラムをジメチルアセトアミド７９．４グラムに溶かした溶液を加えた。次いで、蒸留水２４０．２グラムを加え、内容物を１０〜３０℃で３０分間以上混合した。メチルｔ−ブチルエーテル１２１．２グラムを加え、混合物を３０分間以上攪拌した。各層に分離させ、水層を捨てた。有機層を、水酸化ナトリウム１６．５グラムと蒸留水１５０．２グラムから調製した水酸化ナトリウム溶液で洗浄した。各層に分離させ、水層を捨てた。有機層を、塩化ナトリウム１６．５グラムと蒸留水１０９．７グラムから調製した塩化ナトリウム溶液で洗浄した。各層に分離させ、水層を捨てた。有機層を、７５℃以下の真空中（５０〜１００ｍｍＨｇ）で蒸留した。残渣を酢酸エチル１９６．５グラムに溶解させた。蒸留水５．０グラムを加えた。
【００３１】
Ｂ．Ｎ−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイル）イミダゾール
酢酸エチル１４７．５グラム中に２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチル酪酸（米国特許第５，９１４，３３２号）２４．８グラムおよびカルボニルジイミダゾール２１．０グラムを含む混合物を、１５〜２５℃で１時間以上攪拌した。
【００３２】
Ｃ．（２Ｓ，３Ｓ，５Ｓ）−２−Ｎ，Ｎ−ジベンジルアミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイル）アミノ−１，６−ジフェニルヘキサン
実施例１ステップＢから得られた溶液に蒸留水０．６グラムを加え、内容物を１５分間以上攪拌した。実施例１ステップＡから得られた溶液を、還流するまで加熱した。この実施例１ステップＡから得られた還流溶液を含んだフラスコに、実施例１ステップＢから得られた溶液を移し、還流しながら１時間以上攪拌した。反応物を室温に冷却し、蒸留水２４６．２グラムを加えた。この溶液を１５分間以上攪拌し、水層を分離し、廃棄した。洗浄の度に２４６．２グラムの蒸留水を使用して、有機層をさらに３回洗浄した。次いで、７５℃以下の真空中（５０〜１００ｍｍＨｇ）で有機層を蒸留すると、所望の生成物が得られた。
【００３３】
実施例２
（（２Ｓ，３Ｓ，５Ｓ）−２−（２，６−ジメチルフェノキシアセチル）−アミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロピリミド−２−オニル）−３−メチル−ブタノイル）アミノ−１，６−ジフェニルヘキサン
Ａ．（２Ｓ，３Ｓ，５Ｓ）−２−アミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイル）アミノ−１，６−ジフェニルヘキサン
必要なら５５℃に加熱しながら、実施例１ステップＣの生成物をメタノール３０７．５グラムに溶解させた。この溶液に、ギ酸アンモニウム２１．８グラムおよびパラジウム担持炭素６．９グラムを加えた後、反応物を５０〜６０℃で２時間以上攪拌した。内容物を、濾過助剤パッドを通して濾過した。フラスコおよび濾紙をメタノール８５．６グラムで濯いだ。濾液を合わせて、７５℃以下の真空中（５０〜１００ｍｍＨｇ）で蒸留した。必要なら５０℃に加熱しながら、残渣を酢酸エチル１７１．３グラムに溶解させ、７５℃以下の真空中（５０〜１００ｍｍＨｇ）で濃縮した。必要なら５０℃に加熱しながら、残渣を酢酸エチル２６２．１グラムに溶解させた。試料の水分を分析して、０．２％の限界点に達するようにし、その限界点に達していなければ、蒸留および酢酸エチルの添加を繰り返した。溶媒を蒸留して、所望の化合物を得た。
【００３４】
Ｂ．（２Ｓ，３Ｓ，５Ｓ）−２−アミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイル）アミノ−１，６−ジフェニルヘキサン（Ｓ−ピログルタミン酸塩）
必要なら５０℃に加熱しながら、実施例２ステップＡの生成物を酢酸エチル２６２．１グラムに溶解させた。ジメチルホルムアミド７９．６グラムを加え、溶液を５２℃に加熱した。温度を５２℃に保ちながら、Ｓ−ピログルタミン酸１４．６グラムをジメチルホルムアミド３０．０グラムに溶かした溶液を加えた。ピログルタミン酸塩が沈殿するまで、混合物を５２℃で攪拌した。沈殿し始めない場合、（２Ｓ，３Ｓ，５Ｓ）−２−アミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイル）アミノ−１，６−ジフェニルヘキサン（Ｓ−ピログルタミン酸塩）種晶（米国特許第５，９１４，３３２号）０．０５グラムを使用して、バッチに添加してよい。沈殿し始めたら、バッチを５２℃で１時間以上攪拌し、次いで、２０℃に冷却し、５時間以上攪拌した。沈殿を濾過によって収集し、酢酸エチル１２８．５グラムで洗浄した。真空炉中、６５℃以下の真空中（５０〜１００ｍｍＨｇ）で固体を乾燥すると、所望の化合物５５．６グラムが得られた。
【００３５】
Ｃ．（（２Ｓ，３Ｓ，５Ｓ）−２−（２，６−ジメチルフェノキシアセチル）−アミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロピリミド−２−オニル）−３−メチル−ブタノイル）アミノ−１，６−ジフェニルヘキサン
米国特許第５，９１４，３３２号に記載の方法に従って、実施例２ステップＢの生成物と２，６−ジメチルフェノキシアセチルクロリドを反応させて、所望の生成物を得た。
【００３６】
実施例３
（２Ｓ，３Ｓ，５Ｓ）−２−アミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイル）アミノ−１，６−ジフェニルヘキサン
Ａ．（２Ｓ，３Ｓ，５Ｓ）−２−Ｎ，Ｎ−ジベンジルアミノ−３−ヒドロキシ−５−アミノ−１，６−ジフェニルヘキサン
反応器Ａ（１，０００Ｌ、ガラスライニング製）にエチレングリコールジメチルエーテル５６０Ｌを投入した。攪拌する間、反応器の内容物を５℃以下に冷却した。反応器Ｂ（１０，０００Ｌ、ステンレス鋼製）に水素化ホウ素ナトリウム１０４ｋｇを投入した。水素化ホウ素ナトリウムの塊は、砕いてから反応器に投入した。水素化ホウ素ナトリウムが入っている反応器Ｂにエチレングリコールジメチルエーテル２４００Ｌを投入した。攪拌する間、反応器Ｂの内容物を−１０℃以下に冷却した。添加する間、内部温度を３０℃以下に保ちながら、反応器Ａにメタンスルホン酸６２４ｋｇを投入した。
【００３７】
窒素雰囲気下、反応器Ｃ（３，５００Ｌ、ステンレス鋼製）に２−アミノ−５−Ｓ−ジベンジルアミノ−４−オキソ−１，６−ジフェニルヘキサ−２−エン４００ｋｇを投入した。これにエチレングリコールジメチルエーテル８５０Ｌを投入した。これにイソプロピルアルコール５１０Ｌも投入した。この反応器Ｃの内容物を、固体が溶解するまで混合した。
【００３８】
反応器Ｂの温度を５℃以下に保ちながら、反応器Ａの内容物を反応器Ｂに移した。反応器Ｂの温度を２５℃以下に保ちながら、反応器Ｃの内容物を反応器Ｂに移した。加え終えてから、反応器Ｂの内容物の温度を調節して２０℃±５℃とした。
【００３９】
反応器Ｃにエチレングリコールジメチルエーテル２５０Ｌを投入し、次いで、反応器Ｃの内容物を反応器Ｂに移した。反応器Ｂの内容物を２０℃±５℃で６時間以上攪拌した。次に反応器Ｂの内容物を−３℃以下に冷却した。
【００４０】
窒素雰囲気中で、反応器Ｃに水素化ホウ素ナトリウム５７ｋｇを投入した。水素化ホウ素ナトリウムの塊は、砕いてから反応器に投入した。ポンプを使用して、反応器Ｃに、攪拌しながらジメチルアセトアミド６３５ｋｇを投入した。反応器Ｂの内容物の温度を５℃以下に保ちながら、ポンプを使用して、反応器Ｂにトリエタノールアミン４２４ｋｇを投入した。加え終えてから、反応器Ｂの内容物を−３℃以下に冷却した。
【００４１】
反応器Ｂの内容物の温度を１０℃以下に保ちながら、反応器Ｃの内容物を反応器Ｂに移した。加え終えてから、反応器Ｂの内容物の温度を調節して１５℃±５℃とし、１５℃±５℃で１時間以上攪拌した。
【００４２】
窒素雰囲気中で、反応器Ｄ（１２，０００Ｌ、ステンレス鋼製）に水１９２０Ｌを投入し、反応器ジャケットを５℃±５℃に冷却した。反応器Ｄの内容物を攪拌しながら、反応器Ｂの内容物を反応器Ｄに移し、その間、反応器Ｄの内容物の温度は３０℃以下に保った。反応器Ｂにエチレングリコールジメチルエーテル１００Ｌを投入し、次いで反応器Ｂの内容物を反応器Ｄに移した。
【００４３】
反応器Ｄの内容物を２０℃±５℃で３０分間以上攪拌した。次いで攪拌を止め、反応器Ｄの内容物を１時間以上かけて沈降させた。反応器Ｄの下層を反応器Ｅ（１，０００Ｌ、ステンレス鋼製）中に分離した。反応器Ｅにメチルｔｅｒｔ−ブチルエーテル１３１０Ｌを投入し、反応器Ｅの内容物を２０℃±５℃で１５分間以上攪拌した。攪拌した後、反応器Ｅの内容物を１時間以上かけて沈降させた。反応器Ｅ内の下層を分離し、除去した。
【００４４】
反応器Ｅの内容物を反応器Ｄに移した。反応器Ｄの内容物を１５分間以上攪拌した。攪拌し終えてから、反応器Ｄの内容物を１５分間以上かけて沈降させた。反応器Ｄ内の下層を分離し、除去した。
【００４５】
反応器Ｅに水１２００Ｌを投入した。反応器Ｅに水酸化ナトリウムペレット１３２ｋｇを投入した。固体がすべて溶解するまで反応器Ｅの内容物を攪拌した。
【００４６】
反応器Ｅの内容物を反応器Ｄに移し、反応器Ｄの内容物を１５分間以上攪拌した。次いで、反応器Ｄの内容物を１５分間以上かけて沈降させた。反応器Ｄの下方の水層を分離し、除去した。
【００４７】
反応器Ｅに水８８０Ｌを投入した。反応器Ｅに塩化ナトリウム１３２ｋｇを投入してから、固体がすべて溶解するまで攪拌した。次いで、反応器Ｅの内容物を反応器Ｄに移した。反応器Ｄの内容物を１５分間以上攪拌し、次いで３０分間以上かけて沈降させた。反応器Ｄ内の下層を分離し、除去した。
【００４８】
真空中（５０〜１００ｍｍＨｇ）、７５℃の最高ジャケット温度で、それ以上蒸留できなくなるまで反応器Ｄの内容物を蒸留した。反応器Ｄに酢酸エチル１７４０Ｌを投入し、固体がすべて溶解するまで５０℃以下で攪拌した。固体がすべて溶解したとき、反応器Ｄの内容物を２０℃±５℃に冷却した。
【００４９】
Ｂ．Ｎ−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイル）イミダゾール
窒素雰囲気中で、反応器Ｇ（６，０００Ｌ、ガラスライニング製）に、Ｎ−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタン酸（米国特許第５，９１４，３３２）１９９ｋｇを投入した。これにカルボニルイミダゾール１７５ｋｇを投入した。これに酢酸エチル１３２０Ｌも投入し、その内容物を２０℃±５℃で１時間以上攪拌した。
【００５０】
Ｃ．（２Ｓ，３Ｓ，５Ｓ）−２−アミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイル）アミノ−１，６−ジフェニルヘキサン
反応器Ｄに水３０ｋｇを投入し、この内容物を１０分間以上攪拌した。次いで、反応器Ｄの温度を調節して、還流するようにした（およそ７５〜７７℃）。反応器Ｄの内容物が還流するようになってから、反応器Ｇに水４．６ｋｇを投入し、その内容物を１５分間以上攪拌した。次いで、反応器Ｇの内容物を反応器Ｄに移した。反応器Ｇに酢酸エチル４３０Ｌを投入し、次いで反応器Ｇの内容物を反応器Ｄに移した。次に、反応器Ｄの温度を、内容物が還流するように再度調節した。反応器Ｄの内容物を、還流させながら１時間以上攪拌した。
【００５１】
反応器Ｄに水１９７０Ｌを投入した。反応器Ｄの内容物が４０℃±５℃の温度範囲まで冷えるのを待ち、この内容物を１５分間以上攪拌し続けた。次いで、この内容物を３０分間以上かけて沈降させた。反応器Ｄ内の下層を分離し、除去した。
【００５２】
反応器Ｄに水１９７０Ｌを投入した。反応器Ｄの内容物が４０℃±５℃の温度範囲まで冷えるのを待ち、この内容物を１５分間以上攪拌し続けた。次いで、この内容物を３０分間以上かけて沈降させた。反応器Ｄ内の下層を分離し、除去した。
【００５３】
反応器Ｄに水１９７０Ｌを投入した。反応器Ｄの内容物が４０℃±５℃の温度範囲まで冷えるのを待ち、この内容物を１５分間以上攪拌し続けた。次いで、この内容物を３０分間以上かけて沈降させた。反応器Ｄ内の下層を分離し、除去した。
【００５４】
最高ジャケット温度が７５℃、かつ内部温度が５０℃以下の真空中（５０〜１００ｍｍＨｇ）で、それ以上蒸留できなくなるまで反応器Ｄの内容物を蒸留すると、（２Ｓ，３Ｓ，５Ｓ）−２−Ｎ，Ｎ−ジベンジルアミノ−３−ヒドロキシ−５−（２Ｓ−（１−テトラヒドロ−ピリミド−２−オニル）−３−メチルブタノイル）アミノ−１，６−ジフェニルヘキサンが得られた。
【００５５】
反応器Ｄにメタノール３１１０Ｌを投入し、固体がすべて溶解するまで５５℃±５℃で攪拌した。これにギ酸アンモニウム１７４ｋｇを投入し、固体がすべて溶解するまで５５℃±５℃で攪拌した。
【００５６】
窒素雰囲気中で、反応器Ｈ（８，０００Ｌ、グラスライニング製）にパラジウム担持炭素（水分５０％の５％Ｐｄ／Ｃ）５５ｋｇを投入した。次いで反応器Ｈを２度排気し、それに窒素を充填した。窒素雰囲気を維持しながら、反応器Ｄの内容物を反応器Ｈに移した。反応器Ｄにメタノール２２０Ｌを投入し、次いで反応器Ｄの内容物を反応器Ｈに移した。反応器Ｈの内容物を５５℃±５℃に加熱し、５５℃±５℃で２時間以上攪拌した。次いで、反応器Ｈのジャケット温度を調節して４５℃±５℃とした。
【００５７】
反応器Ｈの内容物を、マルチプレートフィルタ（珪藻土）を通して反応器Ｉ中へ熱濾過した。真空中（５０〜１００ｍｍＨｇ）（ジャケット温度７５℃以下かつ内部温度５０℃以下）で、反応器Ｉの内容物をそれ以上蒸留できなくなるまで還流させた。
【００５８】
次いで、反応器Ｉに酢酸エチル１５２０Ｌを投入し、固体がすべて溶解するまで内容物を４５℃±５℃で攪拌し、真空中（５０〜１００ｍｍＨｇ）（ジャケット温度７５℃以下かつ内部温度５０℃以下）で、それ以上蒸留できなくなるまでこの内容物を還流させて、標題の化合物を得た。
【００５９】
前述の事項は、単に本発明の例に過ぎず、本発明を、開示した諸実施形態に限定するものではない。当分野の技術者に明らかなバリエーションおよび変更は、添付の特許請求の範囲で定義する本発明の範囲の内にあるものとする。[0001]
Technical field
The present invention relates to methods and intermediates used for the synthesis of HIV protease inhibitors.
[0002]
Background of the Invention
Compounds that are protease inhibitors of human immunodeficiency virus (HIV) are useful for inhibiting HIV protease in vitro and in vivo, and are also useful for suppressing HIV infection. Examples of HIV protease inhibitors include compounds of Formula I:
[0003]
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[0004]
Useful intermediates for the preparation of compounds of formula I and analogs thereof are compounds of formula II:
[0005]
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[0006]
Methods for preparing compounds of formula II are disclosed in U.S. Patent No. 5,914,332. The method comprises reacting a compound of formula III
[0007]
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[0008]
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[0009]
Preferred compounds of formula III are P 1 And P 2 Is an N protecting group. The most preferred compound of formula III is P 1 And P 2 Are both benzyl. Most preferred is a compound of formula III which is (2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane.
[0010]
Preferred compounds of formula IV are 3 Is lower alkyl. The most preferred compound of formula IV is R 3 Is isopropyl. Also preferred are acid chloride derivatives of the compound of formula IV. Most preferred is the compound of formula IV which is 2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutyric acid and 2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl A compound of formula IV that is chloride.
[0011]
The disclosed method uses (2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy- with imidazole as base in a suitable solvent (ethyl acetate or ethyl acetate / DMF). 5-Amino-1,6-diphenylhexane is reacted with 2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl chloride. However, this method is not suitable for large-scale production for a number of reasons, including intermediate instability, low yield, and catalyst poisoning. In particular, the acid chloride is relatively unstable, and the use of thionyl chloride in the preparation of the acid chloride results in impurities that poison the catalyst used in subsequent reactions. Furthermore, under the reaction conditions employed, some racemization of the amino acid side chains occurs.
[0012]
Accordingly, there is still a need for improved methods for preparing intermediates for use in the synthesis of HIV protease inhibitors comprising a compound of formula I as defined above.
[0013]
Disclosure of the invention
The present invention provides a compound of formula II
[0014]
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[0015]
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Compound of Formula V
[0016]
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[0017]
In a preferred method of the invention, P 1 And P 2 Is an N protecting group; 3 Is lower alkyl; R 4 Is imidazolyl. In the most preferred method of the present invention, P 1 And P 2 Are both benzyl and R 3 Is isopropyl and R 4 Is imidazolyl.
[0018]
In the process of the present invention, the compound of formula III and the compound of formula V are reacted in a molar ratio of about 1.0 mole of the compound of formula III to about 1.3 mole of the compound of formula V. Preferred ratios are from about 1.0 to about 1.2. The most preferred ratio is from about 1.0 to about 1.15.
[0019]
Suitable solvents for the process of the present invention are inert solvents such as isopropyl acetate, ethyl acetate, tetrahydrofuran (THF), methyl t-butyl ether. A preferred solvent for the method of the present invention is ethyl acetate.
[0020]
The method of the present invention can be performed at a temperature from about 15C to about 100C. The preferred temperature for the process of the present invention is around the reflux temperature of the solvent. The most preferred temperature for the method of the present invention is from about 75 ° C to about 80 ° C.
[0021]
The method of the present invention is accelerated in the presence of water. The preferred amount of water present in the reaction mixture is from about 1% to about 3% (weight / volume) in a ratio of the amount of water (grams) to the total volume of the reaction mixture (mL).
[0022]
The compound of formula V can be prepared in an inert aprotic solvent, such as isopropyl acetate, ethyl acetate, tetrahydrofuran (THF), methyl t-butyl ether, at a temperature of about 15 ° C. to about 50 ° C., and a carboxylic acid IV (about 1. 00 mol) and carbonyldiimidazole (about 1.05 mol). At about 15 ° C. in ethyl acetate, the carboxylic acid IV and R 4 -C (O) -R 4 , R 4 -C (S) -R 4 Or R 4 -S (O) -R 4 [Wherein, R 4 Is as defined above] (preferably carbonyldiimidazole).
[0023]
Although the compound of formula V can be isolated, it is preferred that it be prepared and then reacted (without isolation and purification) with the compound of formula III in a one-pot process.
[0024]
Then P 1 And P 2 Can be debenzylated, and the resulting P 1 And P 2 Reacting a compound of formula II (as (S) -pyroglutamate), each with hydrogen, with 2,6-dimethylphenoxyacetyl chloride (as disclosed in US Pat. No. 5,914,332) Then, lopinavir can be obtained.
[0025]
As used herein, the term "lower alkyl" refers to a straight or branched chain hydrocarbon group containing 1 to 6 carbon atoms. Representative examples of lower alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl n-pentyl, 1-methyl-butyl, 2,2-dimethylbutyl , 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
[0026]
As used herein, the term "cycloalkyl" refers to an aliphatic ring system having 3-10 carbon atoms and one or two rings. Representative cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo [2.2.2] octane, and the like.
[0027]
As used herein, the term "(cycloalkyl) alkyl" refers to a cycloalkyl group attached to a lower alkyl group. Representative examples of (cycloalkyl) alkyl groups include, for example, groups such as cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
[0028]
As used herein, the term "N-protecting group" or "N-protected" refers to a group intended to protect the N-terminus of an amino acid or peptide, or to protect an amino group from undesired reactions during synthetic procedures. . Commonly used N protecting groups are described in T.W. H. Greene and P.M. G. FIG. M. Wuts, "Protective Groups in Organic Synthesis," Second Edition, New York, published by John Wiley & Sons (1991). N protecting groups include formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, Acyl groups such as -chlorobenzoyl, 4-bromobenzoyl and 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl and p-toluenesulfonyl; phenylsulfenyl (phenyl-S-) and triphenylmethylsulfenyl (trityl-S- ) And the like; a sulfinyl group such as p-methylphenylsulfinyl (p-methylphenyl-S (O)-) and t-butylsulfinyl (t-Bu-S (O)-); benzyloxycarbonyl, p -Chlorobenzyloxy Carbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1- Methylethoxycarbonyl, α, α-dimethyl-3,5-dimethoxybenzyloxy-carbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxy-carbonyl, isopropyl Cicarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxy Carbamate-forming groups such as carbonyl and phenylthiocarbonyl; benzyl, p-methoxybenzyl, triphenylmethyl, benzyloxymethyl and the like; alkyl groups; p-methoxyphenyl and the like; and silyl groups such as trimethylsilyl. Preferred N protecting groups include benzyl and the like.
[0029]
Hereinafter, the present invention will be further described with reference to examples.
[0030]
Example 1
(2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5- (2S- (1-tetrahydropyrimid-2-onyl) -3-methylbutanoyl) amino-1,6 -Diphenylhexane
A. (2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane
11.5 grams of sodium borohydride was suspended in 292 grams of ethylene glycol dimethyl ether (DME) and cooled to above -5C. In a separate flask, 70.4 grams of methanesulfonic acid (MSA) was slowly added to 28.0 grams of ethylene glycol dimethyl ether maintained at a temperature below 35 ° C. This MSA solution was cooled to 25 ° C. or lower and transferred to a sodium borohydride suspension maintained at a temperature of 5 ° C. or lower. In a separate flask, 2-amino-5S-dibenzylamino-4-oxo-1,6-diphenylhexane (US Pat. No. 5,491) in a mixture of 91.7 grams of ethylene glycol dimethyl ether and 50.0 grams of isopropyl alcohol. , No. 253) was dissolved in 50 gm. This solution was transferred to a sodium borohydride / MSA solution keeping the temperature below 25 ° C. The contents of the flask were stirred at 15-25 ° C for 1 hour or more. The contents were then cooled to -3 ° C or less, and 53.0 grams of triethanolamine was added while maintaining the temperature at 5 ° C or less. The mixture was stirred for 15 minutes or longer, and a solution of 7.1 g of sodium borohydride in 79.4 g of dimethylacetamide was added while maintaining the temperature at 10 ° C. or lower. Then, 240.2 grams of distilled water was added and the contents were mixed at 10-30 ° C for more than 30 minutes. 121.2 grams of methyl t-butyl ether was added and the mixture was stirred for more than 30 minutes. The layers were separated and the aqueous layer was discarded. The organic layer was washed with a sodium hydroxide solution prepared from 16.5 grams of sodium hydroxide and 150.2 grams of distilled water. The layers were separated and the aqueous layer was discarded. The organic layer was washed with a sodium chloride solution prepared from 16.5 grams of sodium chloride and 109.7 grams of distilled water. The layers were separated and the aqueous layer was discarded. The organic layer was distilled in a vacuum (50-100 mmHg) below 75 ° C. The residue was dissolved in 196.5 grams of ethyl acetate. 5.0 grams of distilled water was added.
[0031]
B. N- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) imidazole
24.8 grams of 2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutyric acid (U.S. Pat. No. 5,914,332) and 21.0 grams of carbonyldiimidazole in 147.5 grams of ethyl acetate. The mixture was stirred at 15-25 ° C. for 1 hour or more.
[0032]
C. (2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) amino-1,6 -Diphenylhexane
Example 1 0.6 g of distilled water was added to the solution obtained from step B and the contents were stirred for more than 15 minutes. Example 1 The solution obtained from step A was heated to reflux. The solution obtained from Step B of Example 1 was transferred to a flask containing the refluxed solution obtained from Step A of Example 1 and stirred for 1 hour or more while refluxing. The reaction was cooled to room temperature and 246.2 grams of distilled water was added. The solution was stirred for more than 15 minutes, the aqueous layer was separated and discarded. The organic layer was washed three more times using 246.2 grams of distilled water for each wash. The desired product was then obtained by distilling the organic layer in a vacuum at 75 ° C. or lower (50-100 mmHg).
[0033]
Example 2
((2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) -amino-3-hydroxy-5- (2S- (1-tetrahydropyrimid-2-onyl) -3-methyl-butanoyl) Amino-1,6-diphenylhexane
A. (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) amino-1,6-diphenylhexane
The product of Example 1, Step C, was dissolved in 307.5 grams of methanol, heating to 55 ° C. if necessary. After adding 21.8 grams of ammonium formate and 6.9 grams of palladium on carbon to the solution, the reaction was stirred at 50-60 ° C. for 2 hours or more. The contents were filtered through a filter aid pad. The flask and filter paper were rinsed with 85.6 grams of methanol. The combined filtrates were distilled in a vacuum (50-100 mmHg) below 75 ° C. The residue was dissolved in 171.3 grams of ethyl acetate, heating to 50 ° C. if necessary, and concentrated in vacuo (50-100 mmHg) below 75 ° C. The residue was dissolved in 262.1 grams of ethyl acetate, heating to 50 ° C. if necessary. The water content of the sample was analyzed to reach the 0.2% threshold, if not, the distillation and addition of ethyl acetate were repeated. The solvent was distilled to obtain the desired compound.
[0034]
B. (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) amino-1,6-diphenylhexane (S- Pyroglutamate)
The product of Example 2, Step A, was dissolved in 262.1 grams of ethyl acetate, heating to 50 ° C. if necessary. 79.6 grams of dimethylformamide were added and the solution was heated to 52 ° C. While maintaining the temperature at 52 ° C., a solution of 14.6 g of S-pyroglutamic acid dissolved in 30.0 g of dimethylformamide was added. The mixture was stirred at 52 ° C. until pyroglutamate precipitated. If precipitation does not begin, (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) amino-1,6 0.05 g of diphenylhexane (S-pyroglutamate) seed (U.S. Pat. No. 5,914,332) may be used to add to the batch. Once precipitation began, the batch was stirred at 52 ° C. for at least 1 hour, then cooled to 20 ° C. and stirred for at least 5 hours. The precipitate was collected by filtration and washed with 128.5 grams of ethyl acetate. Drying of the solid in a vacuum oven under vacuum at 65 ° C. (50-100 mmHg) gave 55.6 grams of the desired compound.
[0035]
C. ((2S, 3S, 5S) -2- (2,6-dimethylphenoxyacetyl) -amino-3-hydroxy-5- (2S- (1-tetrahydropyrimid-2-onyl) -3-methyl-butanoyl) Amino-1,6-diphenylhexane
The product of Example 2, Step B, was reacted with 2,6-dimethylphenoxyacetyl chloride according to the method described in US Pat. No. 5,914,332 to give the desired product.
[0036]
Example 3
(2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) amino-1,6-diphenylhexane
A. (2S, 3S, 5S) -2-N, N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane
560 L of ethylene glycol dimethyl ether was charged into a reactor A (1,000 L, manufactured by glass lining). While stirring, the contents of the reactor were cooled to below 5 ° C. 104 kg of sodium borohydride was charged into a reactor B (10,000 L, made of stainless steel). The mass of sodium borohydride was crushed before being charged into the reactor. 2400 L of ethylene glycol dimethyl ether was charged into reactor B containing sodium borohydride. While stirring, the contents of reactor B were cooled to below -10C. During the addition, 624 kg of methanesulfonic acid was charged into reactor A while maintaining the internal temperature at 30 ° C. or lower.
[0037]
Under a nitrogen atmosphere, 400 kg of 2-amino-5-S-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene was charged into a reactor C (3,500 L, made of stainless steel). To this, 850 L of ethylene glycol dimethyl ether was charged. 510 L of isopropyl alcohol was also added thereto. The contents of reactor C were mixed until the solids dissolved.
[0038]
The contents of the reactor A were transferred to the reactor B while maintaining the temperature of the reactor B at 5 ° C. or lower. The contents of the reactor C were transferred to the reactor B while maintaining the temperature of the reactor B at 25 ° C. or lower. After the addition was completed, the temperature of the contents of the reactor B was adjusted to 20 ° C. ± 5 ° C.
[0039]
Reactor C was charged with 250 L of ethylene glycol dimethyl ether, and then the contents of Reactor C were transferred to Reactor B. The contents of reactor B were stirred at 20 ° C. ± 5 ° C. for 6 hours or more. Next, the content of the reactor B was cooled to −3 ° C. or less.
[0040]
In a nitrogen atmosphere, 57 kg of sodium borohydride was charged into the reactor C. The mass of sodium borohydride was crushed before being charged into the reactor. Using a pump, 635 kg of dimethylacetamide was charged into reactor C with stirring. While maintaining the temperature of the contents of the reactor B at 5 ° C. or lower, 424 kg of triethanolamine was charged into the reactor B using a pump. After the addition was completed, the content of the reactor B was cooled to −3 ° C. or less.
[0041]
The contents of the reactor C were transferred to the reactor B while maintaining the temperature of the contents of the reactor B at 10 ° C. or lower. After the addition was completed, the temperature of the contents of the reactor B was adjusted to 15 ° C. ± 5 ° C., followed by stirring at 15 ° C. ± 5 ° C. for 1 hour or more.
[0042]
In a nitrogen atmosphere, 1920 L of water was charged into a reactor D (12,000 L, made of stainless steel), and the reactor jacket was cooled to 5 ° C. ± 5 ° C. While stirring the contents of Reactor D, the contents of Reactor B were transferred to Reactor D, while keeping the temperature of the contents of Reactor D below 30 ° C. The reactor B was charged with 100 L of ethylene glycol dimethyl ether, and then the contents of the reactor B were transferred to the reactor D.
[0043]
The contents of Reactor D were stirred at 20 ° C. ± 5 ° C. for more than 30 minutes. Then, the stirring was stopped, and the contents of the reactor D were allowed to settle over 1 hour. The lower layer of reactor D was separated into reactor E (1,000 L, made of stainless steel). 1310 L of methyl tert-butyl ether was charged into the reactor E, and the content of the reactor E was stirred at 20 ° C. ± 5 ° C. for 15 minutes or more. After stirring, the contents of reactor E were allowed to settle over 1 hour. The lower layer in reactor E was separated and removed.
[0044]
The contents of reactor E were transferred to reactor D. The contents of Reactor D were stirred for more than 15 minutes. After stirring was complete, the contents of reactor D were allowed to settle over a period of 15 minutes or more. The lower layer in reactor D was separated and removed.
[0045]
1200 L of water was charged into the reactor E. 132 kg of sodium hydroxide pellets were charged into the reactor E. The contents of Reactor E were stirred until all solids were dissolved.
[0046]
The contents of reactor E were transferred to reactor D and the contents of reactor D were stirred for at least 15 minutes. The contents of reactor D were then allowed to settle over a period of 15 minutes. The aqueous layer below reactor D was separated and removed.
[0047]
Reactor E was charged with 880 L of water. After 132 kg of sodium chloride was charged into the reactor E, the mixture was stirred until all solids were dissolved. The contents of reactor E were then transferred to reactor D. The contents of reactor D were stirred for at least 15 minutes and then allowed to settle for at least 30 minutes. The lower layer in reactor D was separated and removed.
[0048]
The contents of reactor D were distilled under vacuum (50-100 mmHg) at a maximum jacket temperature of 75 ° C. until no further distillation was possible. 1740 L of ethyl acetate was charged into the reactor D, and the mixture was stirred at 50 ° C. or lower until all solids were dissolved. When all solids had dissolved, the contents of reactor D were cooled to 20 ° C ± 5 ° C.
[0049]
B. N- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) imidazole
In a nitrogen atmosphere, N- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoic acid (US Pat. No. 5,914,332) is added to reactor G (6,000 L, glass lining). 199 kg, 175 kg of carbonylimidazole, 1320 L of ethyl acetate, and the contents were stirred at 20 ° C. ± 5 ° C. for 1 hour or more.
[0050]
C. (2S, 3S, 5S) -2-amino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) amino-1,6-diphenylhexane
30 kg of water was charged into the reactor D, and the content was stirred for 10 minutes or more. The temperature of reactor D was then adjusted to reflux (approximately 75-77 ° C). After the contents of the reactor D began to reflux, 4.6 kg of water was charged into the reactor G, and the contents were stirred for 15 minutes or more. Next, the contents of the reactor G were transferred to the reactor D. Reactor G was charged with 430 L of ethyl acetate, and then the contents of Reactor G were transferred to Reactor D. Next, the temperature of reactor D was readjusted so that the contents were refluxed. The contents of reactor D were stirred at reflux for 1 hour or more.
[0051]
1970 L of water was charged to the reactor D. The contents of reactor D were allowed to cool to a temperature range of 40 ° C. ± 5 ° C., and the contents were continuously stirred for 15 minutes or more. The contents were then allowed to settle for more than 30 minutes. The lower layer in reactor D was separated and removed.
[0052]
1970 L of water was charged to the reactor D. The contents of reactor D were allowed to cool to a temperature range of 40 ° C. ± 5 ° C., and the contents were continuously stirred for 15 minutes or more. The contents were then allowed to settle for more than 30 minutes. The lower layer in reactor D was separated and removed.
[0053]
1970 L of water was charged to the reactor D. The contents of reactor D were allowed to cool to a temperature range of 40 ° C. ± 5 ° C., and the contents were continuously stirred for 15 minutes or more. The contents were then allowed to settle for more than 30 minutes. The lower layer in reactor D was separated and removed.
[0054]
Distilling the contents of Reactor D in a vacuum (50-100 mmHg) with a maximum jacket temperature of 75 ° C. and an internal temperature of 50 ° C. or less until no more can be distilled, (2S, 3S, 5S) -2- N, N-Dibenzylamino-3-hydroxy-5- (2S- (1-tetrahydro-pyrimid-2-onyl) -3-methylbutanoyl) amino-1,6-diphenylhexane was obtained.
[0055]
3110 L of methanol was charged into the reactor D, and the mixture was stirred at 55 ° C. ± 5 ° C. until all solids were dissolved. 174 kg of ammonium formate was added thereto, and the mixture was stirred at 55 ° C. ± 5 ° C. until all solids were dissolved.
[0056]
In a nitrogen atmosphere, 55 kg of palladium-supported carbon (5% Pd / C with a water content of 50%) was charged into a reactor H (8,000 L, manufactured by glass lining). The reactor H was then evacuated twice and filled with nitrogen. The contents of Reactor D were transferred to Reactor H while maintaining a nitrogen atmosphere. Reactor D was charged with 220 L of methanol, then the contents of reactor D were transferred to reactor H. The contents of Reactor H were heated to 55 ° C. ± 5 ° C. and stirred at 55 ° C. ± 5 ° C. for 2 hours or more. Next, the jacket temperature of the reactor H was adjusted to 45 ° C. ± 5 ° C.
[0057]
The contents of Reactor H were hot filtered into Reactor I through a multiplate filter (diatomaceous earth). The contents of Reactor I were refluxed under vacuum (50-100 mmHg) (jacket temperature below 75 ° C. and internal temperature below 50 ° C.) until no further distillation was possible.
[0058]
Then, 1520 L of ethyl acetate is charged into the reactor I, and the contents are stirred at 45 ° C. ± 5 ° C. until all the solids are dissolved, and the mixture is vacuumed (50 to 100 mmHg) (the jacket temperature is 75 ° C. or less and the internal temperature is 50 ° C. or less) ), The contents were refluxed until no further distillation was possible to give the title compound.
[0059]
The foregoing is merely an example of the invention and is not intended to limit the invention to the disclosed embodiments. Variations and modifications apparent to those skilled in the art are intended to be within the scope of the invention as defined in the appended claims.
Claims (13)
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| PCT/US2001/026898 WO2002018349A2 (en) | 2000-08-31 | 2001-08-29 | Process and intermediates for preparing retroviral protease inhibitors |
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